WO2006057503A1 - Nouveaux composes utilises comme agonistes de ppar-gamma et de ppar-alpha, leur procede de preparation, et composition pharmaceutique contenant ces composes - Google Patents

Nouveaux composes utilises comme agonistes de ppar-gamma et de ppar-alpha, leur procede de preparation, et composition pharmaceutique contenant ces composes Download PDF

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WO2006057503A1
WO2006057503A1 PCT/KR2005/003941 KR2005003941W WO2006057503A1 WO 2006057503 A1 WO2006057503 A1 WO 2006057503A1 KR 2005003941 W KR2005003941 W KR 2005003941W WO 2006057503 A1 WO2006057503 A1 WO 2006057503A1
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phenyl
ethoxy
propionic acid
ethoxyimino
oxadiazole
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PCT/KR2005/003941
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English (en)
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Hee Oon Han
Jong Sung Koh
Geun Tae Kim
Seung Hae Kim
Kyoung-Hee Kim
Hee-Kyung Chung
Hyun Mi Lee
Ok Ku Park
Sung Ho Woo
Hyeon Joo Yim
Gwong-Cheung Hur
Hye Jin Kim
Ki Dong Koo
Chang-Seok Lee
Sung Woon Hong
Sung Ho Kim
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Lg Life Sciences, Ltd.
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Publication of WO2006057503A1 publication Critical patent/WO2006057503A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C251/36—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atoms of the oxyimino groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C251/40—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atoms of the oxyimino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a novel compound as an agonist for peroxisome proliferator-activated receptor gamma (PPAR ⁇ ) and alpha (PPAR ⁇ ), processes of preparing the same, and pharmaceutical compositions containing the same as an active agent.
  • PPAR ⁇ peroxisome proliferator-activated receptor gamma
  • PPAR ⁇ peroxisome proliferator-activated receptor gamma
  • PPAR ⁇ peroxisome proliferator-activated receptor gamma
  • PPAR ⁇ peroxisome proliferator-activated receptor gamma
  • PPAR ⁇ peroxisome proliferator-activated receptor gamma
  • PPAR ⁇ peroxisome proliferator-activated receptor gamma
  • PPAR ⁇ alpha
  • Diabetes mellitus has serious effects on people's health and accompanies various complications.
  • Type II diabetes mellitus accounts for 90% or more of total patients with diabetes mellitus.
  • Representative examples of complications accompanying diabetes include hyperlipidemia, obesity, hypertension, retinopathy and renal insufficiency (Paul Zimmer, et al., Nature, 2001, 414, 782).
  • Sulfonylureas (stimulating insulin secretion in pancreatic cells), biguanides (inhibiting glucose production in the liver), ⁇ -glucosidase inhibitors (inhibiting glucose absorption in the intestines), etc. have been used as agents to treat diabetes.
  • PPARy peroxisome proliferator-activated receptor gamma
  • Thiazolidinediones increasing insulin sensitivity
  • these drugs have side effects such as hypoglycemia, weight gain and the like (David E. Moller, Nature, 2001, 414, 821).
  • these agents raise concerns of inducing hypoglycemia. Accordingly, there is a strong need to develop therapeutic agents which can treat hyperglycemia and reduce complications of diabetes mellitus with decreased side effects, without inducing hypoglycemia and weight gain.
  • PPAR ⁇ accelerators it has been found through in vivo testing that PPAR ⁇ accelerators
  • accelerators for human PPAR ⁇ and PPAR ⁇ showed positive effects in various arteriosclerosis animal models, which also suggested the possibility of these compounds being used to treat arteriosclerosis (Li, A.C., et al, J. Clin. Invest. 2000, 106 523, Collins, A., Arterioscler., Thromb., Vase. Biol. 2002, 21, 365-367, Bernadette P. Neve, et al. Biochemical Pharmacology 2000, 60, 1245). Further, since it was reported that PPAR ⁇ accelerators inhibit factors inducing inflammation, the possibility of PPAR ⁇ accelerators being used as therapeutic agents for treatment of inflammation was also suggested.
  • tesaglitazar AZ-242
  • muraglitazar BMS-298585
  • the animal test result ob/ob mouse
  • tesaglitazar showed the excellent effects thereof on treatment of hyperglycemia, hyperinsulinism, and hypertriglyceridmia (B.Bjung et al., J. Lipid Res. 2002, 43, 1855-1863).
  • the weight gain by the action of PPAR accelator is mainly caused by an increse of subcutaneous fat in which secretion of metabolic regulators occurs actively. While such weight gain is accompanied with a decrease of abdominal fat, weight loss is generally recommended for treatment of diabetes, whereby the development of compounds not causing the weight gain is required.
  • the accelerator activating both PPAR ⁇ and PPAR ⁇ without weight gain has also been reported (R. K. Virkramadithyan et al., Obesity Res. 2003, 11, 292-303).
  • FIG. L is a diagram showing the processing of vector pZeo-GAL in Example
  • FIG. 2. is a diagram showing the processing of vector pZeo-GAL-PPAR ⁇ LBD in Example 57(2).
  • FIG. 3. is a diagram showing the processing of vector pZeo-GAL-PPAR ⁇ LBD in Example 57(3).
  • A is substituted or unsubstituted alkyl, heteroalkyl, aromatic or heteroaromatic group
  • D is hydrogen, lower alkyl, phenyl or benzyl group; E and G are each independently hydrogen or lower alkyl group; n is i or 2.
  • the compound of Formula 1 as an active agent for treatment of diseases is intended to include pharmaceutically acceptable salts, or isomers thereof.
  • pharmaceutically acceptable salts, or isomers thereof For the convenience of explanation, they are briefly illustrated as the compound of Formula lin the present disclosure.
  • the compound of Formula 1 according to the present invention has the structure quite different from well-known PPAR ⁇ and PPAR ⁇ accelerators and also an excellent activation effect as to human PPAR ⁇ and PPAR ⁇ associated with prevention and treatment of diabetes mellitus, and complications accompanying diabetes such as hyperlipidemia and arteriosclerosis, and inflammation, as can be seen in the below Experimental Examples,
  • the term "pharmaceutically acceptable salt” means a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
  • the pharmaceutical salts includes salts of acids that form non-toxic acid adduct containing pharmaceutically acceptable anion, for example, acid adducts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, iodic acid and the like; acid adducts of organic carbonic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifiuoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid and the like; acid adducts of sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, bezenesulfonic acid
  • the examples of pharmaceutically acceptable salts of carboxylic acid include metal salts or alkaline earth metal salts of lithium, sodium, potassium, calcium magnesium and the like; and salts of amino acids such as lysine, arginine, guanidine and the like; organic salts of dicyclohexylamine, N-methyl-D-glucarmine, tris(hydroxymethyl)rnethylamine, diethanolamine, choline, tirethylamine and the like.
  • the compound of Formula 1 according to the present invention can be converted to its salts by known methods.
  • the term "isomer” means a compound of the present invention or a salt thereof, that has the same chemical formula or molecular formula but is optically or stereochemically different therefrom. Since a variety of compounds according to the present invention have an asymmetric carbon center, they can be present in the form of R or S isomers, and/or oxime geometric isomers (trans, cis). All of these isomers and mixtures thereof are of course included in the range of the present invention.
  • 'A' in Formula 1 above is preferably selected from the below substitutents: (i) lower alkyl substituted or unsubstituted by alkoxy, halogen or CF 3 ; (ii) phenyl or benzyl substituted or unsubstituted by lower alkyl, alkoxy, halogen or CF 3 ;
  • X is N or C
  • Rl is each independently one of the below substituents
  • R2, R3 and R4 are each independently hydrogen, halogen or lower alkyl group.
  • lower alkyl is preferably alkyl having carbon atoms less than 7, more preferably, alkyl OfC 1 -C 4 , for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, and the like.
  • the compounds of Formula 1 are compounds as defined below:
  • (+) 3 -(4- ⁇ 2- [(E)-benzyloxyimino] -propoxy ⁇ -phenyl)-2-ethoxy-propionic acid ( ⁇ ) 2-ethoxy-3-(4- ⁇ 2-[(Z)-ethoxyimino]-2-phenyl-ethoxy ⁇ -phenyl)-propionic acid ( ⁇ ) 2-ethoxy-3-(4- ⁇ 2-[(Z)-benzyloxyimino]-2-phenyl-ethoxy ⁇ -phenyl)-propionic acid ( ⁇ ) 2-ethoxy-3-(4- ⁇ 2-[(Z)-hexyloxyimino]-2-phenyl-ethoxy ⁇ -phenyl)-propionic acid ( ⁇ ) 2-ethoxy-3-(4- ⁇ 2-[(Z)-ethoxyimino]-2-naphthalene-2-yl-ethoxy ⁇ -phenyl)-propionic acid
  • the present invention also relates to processes for preparation of the compounds of Formula 1.
  • a person skilled in the art could easily manufacture the compound of Formula 1 on the basis of the chemical structure thereof by various processes.
  • the compound of Formula 1 can be prepared by reacting the compound of Formula 2 with the compound of Formula 3 in the presence of base, as shwon in Reaction Scheme 1 below.
  • Reaction Scheme 1 Reaction Scheme 1
  • Oms (methanesulfonyloxy group).
  • the reaction can be conducted in the presence of organic solvent, such as dimethylformamide, dimethylacetamide and acetonitrile and the like, and in some cases, two or more kinds of them can be used.
  • organic solvent such as dimethylformamide, dimethylacetamide and acetonitrile and the like, and in some cases, two or more kinds of them can be used.
  • the typical examples of the base includes sodium hydroxide, potassium t-butoxide, cesium carbonate, potassium carbonate, sodium carbonate, potassium bis (trimethylsilyl) amide and the like, and in some cases, two or more kinds of them can be used.
  • the desired compound of Formula 1 can be prepared by hydrolyzing condensed compounds.
  • the compound of Formula 3 above can be prepared by the known method (Ansersson, Kj ell: WO99/62872).
  • the compound of Formula 2 above can also be
  • A, D, E, G, and n are the same as defined in Formula 1, and X means Cl, Br, I or Oms (methanesulfonyloxy group).
  • the oximation 'a' in the reaction scheme can be conducted with oxime in the presence of organic solvent, such as methanol, ethanol or propanol, or even water, and in some cases, two or more mixtures of them can be used.
  • organic solvent such as methanol, ethanol or propanol, or even water, and in some cases, two or more mixtures of them can be used.
  • the typical examples of the base include sodium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate and the like, and in some cases, two or more kinds of them can be used.
  • the reaction 'b' can be conducted with hydrazide 6 in the presence of organic solvent, such as dimethylformamide, dichloromethane, acetonitrile or dimethylsulfoxide, and in some cases, 2-chloro-l,3-dimethylimidazolium chloride can be used in the presence of two or more kinds of the organic solvents to prepare the compound of Formula 8 via the compound of Formula 7
  • organic solvent such as dimethylformamide, dichloromethane, acetonitrile or dimethylsulfoxide
  • 2-chloro-l,3-dimethylimidazolium chloride can be used in the presence of two or more kinds of the organic solvents to prepare the compound of Formula 8 via the compound of Formula 7
  • the typical examples of the base include triethylamine, diisopropylethylamine, potassium carbonate and the like, and in some cases, two or more kinds of them can be used.
  • D, X and R 1 are the same as defined in Formula 8, and PG means general functional groups which can serve as protector(s) of alchol, such as TBS(t- butyldimethylsiyl), TBDPS(t-butyldiphenylsilyl), Tr(triphenylmethyl), benzyl and the like.
  • the reation 'a' in the reaction scheme can be conducted with oxime in the presence of organic solvent, such as methanol, ethanol or propanol, or even water, and in some cases, two or more kinds of them can be used.
  • organic solvent such as methanol, ethanol or propanol, or even water
  • two or more kinds of them can be used.
  • the typical examples of the base include sodium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate and the like, and in some cases, two or more kinds of them can be used.
  • the reaction 'b' can be conducted with the compound of Formula 11 in the presence of organic solvent, such as dimethylformamide, dichloromethane, acetonitrile or dimethylsulfoxide using 1,1-carbonyldiimide to obtain the compound of Formula 12.
  • organic solvent such as dimethylformamide, dichloromethane, acetonitrile or dimethylsulfoxide using 1,1-carbonyldiimide to obtain the compound of Formula 12.
  • Disprotectation for PG in the compound of Formula 12 is conducted, followed by bromination, indolization, or reaction using methanesulfonylchloride, to synthesize the compound of Formula.
  • the compounds of Formula 13 above can also be prepared by a person skilled in the art on the basis of the chemical structure by various methods.
  • the compound of Formula 1 according to the present invention can also be prepared by a process in which the compound of Formula 14 reacts with the compound of Formula 3 to synthesize the compound of Formula 15, followed by oximation, as shown in Reaction Scheme 4 below.
  • Reaction Scheme 4 Reaction Scheme 4
  • A, D, E, G and n are the same as defined in Formula 1 , and X meana Cl, Br, I or Oms (methanesulfonyloxy group).
  • the reation 'a' in the reaction scheme can be conducted in the presence of organic solvent, such as dimethyformamide, dimethylacetamide, acetonitrile, etc., and in some cases, two or more kinds of them can be used.
  • organic solvent such as dimethyformamide, dimethylacetamide, acetonitrile, etc.
  • the typical examples of the base include sodium hydroxide, potassium t-butoxide, cesiumcarbonate, potassiumcarbonate, sodium carbonate, potassium bis(tremethylsilyl) amide and the like, and in some cases, two or more kinds of them can be used.
  • the oximation 'b' can be conducted with oxime in the presence of organic solvent, such as methanol, ethanol or propanol, or water, and in some cases, two or more kinds of them can be used.
  • organic solvent such as methanol, ethanol or propanol, or water
  • the typical examples of the base include sodium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate and the like, and in some cases, two or more kinds of them can be used.
  • the compounds of Formula 15 above can also be prepared by a person skilled in the art on the basis of the chemical structure by various methods.
  • the present invention provides a pharmaceutical composition for accelerating PPAR ⁇ and PPAR ⁇ comprising (a) a therapeutically effective amount of the compound of Formula 1, and (b) a physiologically acceptable carrier, diluent, or excipient, or a combination thereof.
  • composition means a mixture of a compound of the invention with other chemical components, such as diluents or carriers.
  • the pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to oral, injection, aerosol, parenteral, and topical administrations.
  • Pharmaceutical compositions can also be obtained by reacting compounds with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • a therapeutically effective amount means an amount of active ingredients effective to alleviate, ameliorate or prevent symptoms of disease or decrease or delay the onset of clinical markers or symptoms of disease.
  • a therapeutically effective amount refers to that amount which has the effect of (1) reversing the rate of progress of a disease; (2) inhibiting to some extent progress of the disease; and/or, (3) alleviating to some extent (or, preferably, eliminating) one or more symptoms associated with the disease.
  • the therapeutically effective amount may be determined by experiments on the efficacy of compound as an active agent via in vivo and in vitro known model systems for diseases to be treated.
  • carrier means a chemical compound that facilitates the incorporation of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a commonly utilized carrier as it facilitates the uptake of many organic compounds into the cells or tissues of an organism.
  • DMSO dimethyl sulfoxide
  • diot defines chemical compounds diluted in water that will dissolve the compound of interest as well as stabilize the biologically active form of the compound. Salts dissolved in buffered solutions are utilized as diluents in the art.
  • One commonly used buffered solution is phosphate buffered saline because it mimics the ionic strength conditions of human blood. Since buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely modifies the biological activity of a compound.
  • the compounds described herein can be administered to a human patient per se, or in pharmaceutical compositions in which they are mixed with other active ingredients, as in combination therapy, or suitable carriers or excipient(s). Techniques for formulation and administration of the compounds may be found in "Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, PA, 18th edition, 1990.
  • the pharmaceutical composition of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • compositions for use in accordance with the present invention thus may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well- known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences, above.
  • the compound of Formula 1 according to the present invention can be formulated into dasage forms suitable for injection or oral admimistration in accordance with intended use.
  • the agents of the present invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution,
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compound of the present invention to be formulated as tablet, pill, powder, granule, dragee, capsule, liquid, gel, syrup, slurry, suspension and the like, for oral ingestion by a patient.
  • Preferable dosage forms are capsule and tablet. It is preferable that tablets and pills be coated.
  • Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with one or more compounds of the present invention, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethyl cellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • compositions suitable for use in the present invention include compositions in which the active ingredients are contained in an amount effective to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • the compound of Formula 1 as an active agent can be preferably contained in an amount of about 0.1 ⁇ 1,000 mg unit dosage.
  • the dosage amount of the compound of Formula 1 will be dependent on the subject's weight and age, the nature and severity of the affliction and the judgment of the prescribing physician.
  • the dosage amount required will be in the range of about 1 to 1000 mg a day depending on the frequency and strength of the dosage.
  • a total dosage amount of about 1 ⁇ 500 mg a day will be sufficient. In some patients, the dosage amount in a day will be higher than that.
  • the present invention provides the use of the compound of Formula 1 for manufacture of a medicament for the treatment or prevention of diseases involving human PPAR ⁇ and PP ARa.
  • Diseases involving human PPAR ⁇ and PP ARa mean the diseases which can be treated and prevented by activating human PPAR ⁇ and PP ARa, and include, for example, but are in no way limited to diabetes mellitus, complications associated with diabetes mellitus, inflammation, etc. Representative examples of the complications associated with diabetes mellitus are hyperlipidemia, arteriorasclerosis, obesity, hypertension, retinopathy, kidney inefficiency, etc.
  • the term “treating” means ceasing or delaying progress of diseases when the compound of Formula 1 or composition comprising the same is administered to subjects exhibiting symptoms of diseases.
  • the term “preventing” means ceasing or delaying symptoms of diseases when the compound of Formula 1 or composition comprising the same is administered to subjects exhibiting no symptoms of diseases, but having high risk of developing symptoms of diseases.
  • Example 2 (+) 2-ethoxy-3-(4- ⁇ 2-[(Z)-ethoxyimino]-2-phenyl-ethoxy ⁇ -phenyl)- propionic acid 10 mg (yield: 83%) of the title compound was obtained from 13 mg of the compound obtained in Perparation Example 4 in the same manner as in Example 1.
  • Example 5 ( ⁇ ) 2-ethoxy-3-(4- ⁇ 2-[(Z)-ethoxyimino]-2-naphthalene-2-yl-ethoxy ⁇ - phenyl)-propionic acid 14 mg (yield: 85%) of the title compound was obtained from 2-bromo-l- naphthalene-2-yl-ethanone (6 mg, 0.015 mmol) in the same manner as in Preparation Example 4 and Example 2.
  • Example 7 ⁇ ) 2-ethoxy-3-(4- ⁇ 2-[(E/Z)-ethoxyimmo]-3-phenyI-propoxy ⁇ -phenyI)- propionic acid methylester 18 mg (yield: 26%) of the title compound was obtained from the compound obtained in Preparation Example 7 (35 mg, 0.18 mmol) in the same manner as in Preparation Example 2 and Example 1.
  • Example 12 ( ⁇ ) 3-(4- ⁇ 2-(2,4-dichloro-phenyl)-2-[(Z)-ethoxyimino]-ethoxy ⁇ - phenyl)-2-ethoxy-propionic acid
  • Example 17 ( ⁇ ) 2-ethoxy-3- ⁇ 4-[2-[(Z)-ethoxyimino]-2-(5-methyl-2-thiophene-2-Iy- oxazole-4-yl)-phenyl] -propionic acid 10 mg (yield: 20%) of the title compound was obtained from ( ⁇ ) 2-ethoxy-3-(4- hydroxyphenyl)propionic acid methylester (24 mg, 0.11 mmol) and the compound obtained in Preparation Example 10 (31 mg, 0.11 mmol) in the same manner as in Preparation Example 3, 4 and Example 2.
  • Example 19 ( ⁇ ) 2-ethoxy-3- ⁇ 4-[2-[(E)-ethoxyimino]-2-(5-phenyl-[l,3,4]oxadiazole- 2-yl)-ethoxy] -phenyl ⁇ -propionic acid 4 mg (yield: 38%) of the title compound was obtained from 5 mg (0.024 mmol) of the compound in the Preparation Example 11 in the same manner as in Preparation Example 2 and Example 1.
  • Preparation Example 13 Preparation of methanesulfonic acid 2-(5-phenyI- [l,3 > 4]oxadiazole-2-yl)-2-propoxyimino-ethyl ester 2-hydroxy-l-(5-phenyl-[l,3,4]oxadiazole-2-yl)-propanone O-ethyl-oxime was obtained from 2-(t-butyl-dimethylsilanyloxy)-l-(5-phenyl-[l,3,4]oxadiazole-2-yl)- ethanone in the same manner as in Preparation Example 11(2) and 11(3).
  • Preparation Example 17 Preparation of 2-ethoxy-3-(3- ⁇ 2oxo-2-phenyl-ethoxy ⁇ - phenyl)-propionic acid ethylester 45 mg (yield: 97%) of the title compound was obtained from 2-bromo-l- phenyl-ethanone (26 mg, 0.13 mmol) and 2-ethoxy-3-(3-hydroxy-phenyl)-propionic acid ethylester (30 mg, 0.13 mmol) in the same manner as in Preparation Example 3.
  • Example 28 2-ethoxy-3-(4- ⁇ 2-(ethoxyimino)-2-(4-phenyl-oxazole-2-yl)-ethoxy ⁇ - phenyl)-propionic acid
  • Preparation Example 24 Preparation of 2-ethoxy-3-(3- ⁇ 2-(ethoxyimino)-2-(4- trifluoromethyl-phenyl)-ethoxy ⁇ -phenyl)-propionic acid ethylester 53 mg (yield: 70%) of the title compound was obtained from 2-bromo-l-(4- trifluoromethyl-phenyl)-ethanone O-ethyl-oxime (50 mg, 0.16 mmol) and 2-ethoxy-3- (3-hydroxy-phenyl)-propionic acid ethylester (39 mg, 0.16 mmol) in the same manner as in Preparation Example 3.
  • 4-fluorobenzhydrazide hydrochloride salt (765 mg, 4.0 mmol) and 3-bromo-2- propoxyimino-propionic acid (900 mg, 4.01 mmol) was dissolved in 30 ml of dichloromethane, then triethylamine (1.67 ml, 11.9 mmol) and 2-chloro-l,3- dimethylimidazolium chloride (680 mg, 4.0 mmol) were added thereto at 0°C, followed by stirring for 10 minutes. The resulting solution was allowed to warm to room temperature, then further stirred for 3 hours. 100 ml of ethylacetate was added to thereto, and an organic layer was washed twice with water.
  • Preparation Example 29 Preparation of 2-ethoxy-3-(3- ⁇ 2-[5-(4-fraoro-phenyl)- [1 ,3 » 4] oxadiazole-2-yl] -2-(propoxyimino)-ethoxy ⁇ -pheny)-propionic acid ethylester 230 mg (yield: 46%) of the title compound was obtained from 2-bromo-l-(5-(4- fluoro-phenyl)-[l,3,4]oxadiazole-2-yl)-ethanone O-ethyl-oxime (215 mg, 0.62 mmol) and 2-ethoxy-3-(3-hydroxy-phenyl)-propionic acid ethylester (150 mg, 0.62 mmol) in the same manner as in Preparation Example 3.
  • 3-bromo-2-(propoxyimino)-propionic acid ethylester (420 mg, 1.66 mmol) was dissolved in 5 ml of dimethylformamide, and sodium acetate was added thereto. After heating at 80°C for 5 hours, extraction was conducted with ethylacetate. The extracted solution was dried over anhydrous magnesium sulfate and concentrated then purified by column chromatography to obtain 257 g of the title compound in a yield of 67% yield.
  • 3-hydroxy-2-(propoxyimino)-propionic acid ethylester (110 mg, 0.67 mmol) was dissolved in 3 ml of dimethylformamide, and imidazole (232 mg, 3.40 mmol) was added thereto, then the reaction was cooled to -30°C.
  • t-butyldimethylsilyl chloride (257 mg, 1.70 mmol) was added thereto and stirred for 1 hour, then water was added thereto.
  • the product was extracted with ethylacetate and dried over anhydrous magnesium sulfate to be concentrated.
  • the resulting solution was dissolved in 2 ml of methanol, and potassiumcarbonate (20 mg, 0.14 mmol) was added thereto, then stirred for 2 hours.
  • Example 37 ( ⁇ ) 3-(4- ⁇ [(2E)-2-[5-(4-chlorophenyl)-l,3,4-oxadiazole-2-yl]-2- (ethoxyin ⁇ ino)ethyl] oxy ⁇ phenyl)-2-ethoxypropionic acid 15 mg (yield: 79%) of the title compound was obtained from ( ⁇ ) 3-(4- ⁇ [(2E)-2-
  • Example 38 ( ⁇ ) 3-(3- ⁇ [(2E)-2-[5-(4-chlorophenyl)-l,3,4-oxadiazole-2-yl]-2- (ethoxyimino)ethyI]oxy ⁇ phenyl)-2-ethoxypropionic acid
  • Example 40 ( ⁇ ) 3-(3- ⁇ [(2E)-2-[5-(3-chlorophenyl)-l,3,4-oxadiazole-2-yl]-2- (ethoxyimino)ethyl] oxy ⁇ phenyl)-2-ethoxypropionic acid
  • Preparation Example 52 Preparation of ( ⁇ ) 3-(3- ⁇ [(2E)-2-[3-(4-chlorophenyl)- l,2,4-oxadiazole-5-yl]-2-(propoxyimino)ethyl]oxy ⁇ phenyl)-2-ethoxypropionic acid ethylester 9.0 mg (yield: 65%) of the title compound was obtained from methanesulfonic acid 2-[3-(4-chloro-phenyl)-[l,2,4]oxadiazole-5-yl]-2-propoxyimino-ethyl ester (10 mg, 0.027 mmol) and ( ⁇ ) 2-ethoxy-3-(3-hydroxyphenyl)propionic acid ethylester (6.4 mg, 0.027 mmol) in the same manner as in Preparation Example 3.
  • Preparation Example 64 Preparation of 2-bromo-l-[4-phenoxyphenyl]ethanone l-[4-phenoxyphenyl]ethanone (500 mg, 2.35 mmol) was dissolved in 10 ml of chloroform and 3 ml of methanol, and 1.16 g (2.40 mmol) of tetrabutylammonium tribromide was slowly added dropwise thereto. After stirring for 9 hours, 50 ml of ethylacetate was added thereto, and the reaction was washed with 5% Na 2 S 2 O 3 solution.
  • Example 54 ( ⁇ ) 2-ethoxy-3-(4- ⁇ [(2Z)-2-(2-phenyl-l,3-thiazole-4-yl)-2- (propoxyimino)ethyl]oxy ⁇ phenyl)propionic acid 4.5 mg (yield: 95%) of the title compound was obtained from ( ⁇ ) 2-ethoxy-3-
  • Example 56 Construction of reporter vector containing lucif erase structural gene in GAL4 transcription gene sequence
  • Example 57 Construction of vector expressing fusion protein of GAL4 and ligand- binding domain of PPAR protein
  • a vector expressing a protein in which the DNA-binding domain of GAL4 is fused with the ligand-binding domain of PPAR under control of SV40 promoter, was constructed using pZeoSV (Invitrogen, Cat. No. V85001) being a mammalian cell expression vector as a basic vector.
  • pZeoSV Invitrogen, Cat. No. V85001
  • primer GAL4-HIII (5'-GC AAGCTT GAAGCAAGCCTCCTGAAAG ATG AAG CTA CTG TCT TCT ATC GAA C-3') contains the sequence encoding amino acids 1 to 8 of the N-terminal of the GAL4 DNA-binding domain, and also the restriction enzyme HindIII recognition domain.
  • Another primer GAL4-KI (5'-AA GGTACC GGT AAA TTC CGG CGA TAC AGT CAA CTG TCT TTG A-3 1 ) contains the sequence encoding amino acids 141 to 147 of the C-terminal of the DNA-binding domain of GAL4, and also the restriction enzyme Kpnl recognition domain. 2 ⁇ g of the primer GAL4-HIII and 2 ⁇ g of the primer GAL4-KI were added into a reaction tube, then 10 ng of plasmid pGBT9 (Clonetech, Cat. No.
  • K1605-A as a template, and 10 ⁇ l of 10 x polymerization buffer (50 mM KCl, 100 mM Tris-HCl, pH 9.0, 1% Triton X-100, 2.5 mM MgCl 2 ), 10 ⁇ l of 2 mM dNTP (2 mM dGTP, 2 mM dATP, 2 mM dCTP and 2 mM dTTP), 2.5 units of Taq polymerase, and distilled water were further added to a total volume of 100 ⁇ l, and PCR was carried out for 25 cycles with denaturation at 95°C for 40 seconds, annealing at 55 0 C for 30 seconds, and polymerization at 72°C for 1 minute.
  • 10 x polymerization buffer 50 mM KCl, 100 mM Tris-HCl, pH 9.0, 1% Triton X-100, 2.5 mM MgCl 2
  • 10 ⁇ l of 2 mM dNTP 2
  • 'fragment GAL4-H/K' The DNA fragment thus seperated and purified (hereinafter, referred to as 'fragment GAL4-H/K') was fully restricted with HindIII and Kpnl in NEB buffer 2 (50 mM NaCl, 10 mM Tris-HCl, 10 mM MgC12, 1 mM dithiothreitol (pH 7.9)), and extracted with phenol/chloroform, then eluted with 20 ⁇ l of TE (10 mM Tris-HCl, 1 mM EDTA, pH 8.0) solution.
  • NEB buffer 2 50 mM NaCl, 10 mM Tris-HCl, 10 mM MgC12, 1 mM dithiothreitol (pH 7.9)
  • fragment pZeoSV-H/K 2 ⁇ g of plasmid pZeoSV was fully restricted with restriction enzymes HindIII and Kpnl in NEB buffer 2, and a nucleic acid fragment of about 3.5 kb was seperated and purified in 1% agarose gel.
  • fragment pZeoSV-H/K 2 ⁇ g of plasmid pZeoSV was fully restricted with restriction enzymes HindIII and Kpnl in NEB buffer 2, and a nucleic acid fragment of about 3.5 kb was seperated and purified in 1% agarose gel.
  • Primer GLBD-f (5'-GG GGTACC TCT CAT AAT GCC ATC AGG TTT GGG CGG ATG C -3') contains the sequence encoding from Ser 176 to Met 185 of human PPAR ⁇ gene and also the restriction enzyme Kpnl - recognition domain.
  • Primer GLBD-r (5'-CC ACGCGT CTA GTA CAA GTC CTT GTA GAT CTC C -3') contains the sequence encoding from GIu 472 to Tyr 478 of human PPAR ⁇ gene and the termination codon, allowing the termination of translation at the 478 th amino acid, and also the restriction enzyme MIuI - recognition domain.
  • a DNA fragment encoding from Ser 176 to Tyr 478 containing the human PPAR ⁇ ligand-binding domain was amplified by PCR using the above described primer and also using the full- length cDNA of human PPAR ⁇ , isolated from human liver cDNA library, as a template.
  • fragment pZeoGAL-K/M 2 ⁇ g of plasmid pZeo-GAL obtained above was fully restricted with restriction enzymes Kpnl and MIuI in NEB buffer 2, and a nucleic acid fragment of 4.0 kb was seperated and purified in 1% agarose gel.
  • this fragment is referred to as "fragment pZeoGAL-K/M”.
  • Primer ALBD-f (5'-GG GGTACC TCA CAC AAC GCG ATT CGT T-3') contains the sequence encoding from Ser 167 to Arg 175 of human PPAR ⁇ and also the restriction enzyme Kpnl - recognition domain.
  • Primer ALBD-r (5'-CC ACGCGT TCA GTA CAT GTC CCT GTA GAT CTC CTG C-3 1 ) contains the sequence encoding from GIn 461 to Tyr 468 including the human PPAR ⁇ ligand-binding domain and the termination codon, allowing the termination of translation at the 468 th amino acid, and also the restriction enzyme MIuI - recognition domain.
  • the PCR product was separated in 1% agarose gel, it was confirmed that a DNA fragment of about 900 base pairs was amplified, then the product was seperated and purified from the agarose gel.
  • nucleic acids thus seperated and purified (hereinafter, referred to as 'fragment ALBD-K/M') were fully restricted with restriction enzymes Kpnl and MIuI in NEB buffer 2, and extracted with phenol/chloroform, then eluted with 20 ⁇ l of TE solution.
  • the product was transformed into E.coli HBlOl (ATCC 33694) to obtain the expression vector as desired in which the DNA fragment encoding human PPAR ⁇ ligand-binding domain is inserted into DNA encoding the GAL4 DNA-binding domain of pZeoGAL (hereinafter, referred to as "pZeo-GAL- PPARaLBD").
  • CV-I cells derived from monkey kidney were aliquoted into each well of 24- well plate at a density of 6.OxIO 4 per/well, suspended in DMEM medium (Life Technologies Inc) supplemented with 10% FBS, and cultured for 24 hours at 37°C in 5% CO 2 atmosphere. After culturing, the growth medium was replaced with 200 ⁇ l of OptiMEMTM medium (Life Technologies Inc) and the cells were used for transformation.
  • the amount of DNA was 480 ng of pGL3-GAL4, 48 ng of pZeo-GAL-PPAR ⁇ LBD or pZeo-GAL-PPAR ⁇ LBD and 128 ng of pCHllO (Amersham, Cat.No. 27-4508-01) per well.
  • Example 59 Determination of accelerating activity for human PPAR ⁇ or PPAR ⁇ (1) Measurement of degree of expression of Luciferase
  • the growth medium was removed from the transformed cells of Experimental Example 39, and the compounds of Examples 1 to 55 were suspended in DMSO and added in DMEM medium supplemented with 5% FBS, then the resulting mixture was added to each well, followed by culturing at 37 0 C in 5% CO 2 atmosphere for 24 hours. After the culturing, the culture media was removed and cells were washed twice with PBS (Life Technologies Inc). To each well, 100 ⁇ l of Passive Lysis Buffer (PLB) solution (Promega Corporation) was added and then gently stirred for 20 minutes at room temperature. 20 ⁇ l of cell lysate taken from each well was removed to a Costar 96-well Luminometer and luciferase activity was determined using Luciferase Assay SystemTM kit (Promega Corporation) following the instructions of the manufacturer.
  • PBS Passive Lysis Buffer
  • the efficacy of transformation in cell lysis buffer was represented by the activity of beta-galactosidase measured in the above, and the comparative activity of luciferase was measured, thereby comparing the degree of the activity of each compound.
  • the experimental results were expressed as an increasing multiple on the basis of the value of the control, in which only 5% DMSO without compound was added.
  • EC 5O being the efficacy of the compounds obtained in Examples 1 to 55, was presented in Table 1 and 2 below.
  • EC 5O Effective concentration fifty expresses the concentration of a compound which shows 50% of the maximum possible response of the compound.
  • the compound of Formula 1 according to the present invention is very effective for accelerating the activity of PPAR ⁇ and PPAR ⁇ . Accordingly, the compound according to the present invention can be used as a drug for treatment or prevention of diseases involving human PPAR ⁇ and PPAR ⁇ , for example, diabetes mellitus, complications associated with diabetes mellitus, inflammation, etc.

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Abstract

L'invention concerne de nouveaux composés accélérant l'activité du récepteur gamma et du récepteur alpha, activé par les proliférations des peroxisomes (PPARη) et (PPARα). L'invention concerne également des procédés de préparation de ces composés, ainsi que des compositions pharmaceutiques, utilisées comme agents actifs, contenant ces composés.
PCT/KR2005/003941 2004-11-25 2005-11-22 Nouveaux composes utilises comme agonistes de ppar-gamma et de ppar-alpha, leur procede de preparation, et composition pharmaceutique contenant ces composes WO2006057503A1 (fr)

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AU2010302584B2 (en) * 2009-10-02 2015-09-10 Avexxin As Anti inflammatory 2-oxothiazoles and 2 -oxooxazoles
AU2015268638B2 (en) * 2009-10-02 2017-08-31 Avexxin As Anti inflammatory 2-oxothiazoles and 2-oxooxazoles
EP3135664A4 (fr) * 2014-04-21 2017-11-01 Adeka Corporation Composé alcoxyde, matière première pour former un film mince, procédé de production de film mince, et composé alcool
US10150781B2 (en) 2014-08-01 2018-12-11 Avexxin As 2-oxothiatole compounds having activity as CPLA2 inhibitors for the treatment of inflammatory disorders and hyperproliferative disorders
US10259801B2 (en) 2013-01-29 2019-04-16 Avexxin As Anti-inflammatory and antitumor 2-oxothiazoles ABD 2-oxothiophenes compounds
US11439625B2 (en) 2016-03-14 2022-09-13 Avexxin As Combination therapy for proliferative diseases

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WO2004066963A2 (fr) * 2003-01-17 2004-08-12 Merck & Co., Inc. Derives de n-cyclohexylaminocarbonyl benzenesulfonamide
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WO2002064094A2 (fr) * 2001-02-09 2002-08-22 Merck & Co., Inc. Acides 2-aryloxy-2-arylalcanoïques utilisés pour le traitement du diabètes et des troubles lipidiques
WO2002096358A2 (fr) * 2001-05-30 2002-12-05 Bristol-Myers Squibb Company Derives acides d'azole substitue utiles comme agents antidiabetiques et agents contre l'obesite et procede apparente
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Publication number Priority date Publication date Assignee Title
AU2010302584B2 (en) * 2009-10-02 2015-09-10 Avexxin As Anti inflammatory 2-oxothiazoles and 2 -oxooxazoles
US9597318B2 (en) 2009-10-02 2017-03-21 Avexxin As 2-oxothiazole compounds and method of using same for chronic inflammatory disorders
AU2015268638B2 (en) * 2009-10-02 2017-08-31 Avexxin As Anti inflammatory 2-oxothiazoles and 2-oxooxazoles
US10370344B2 (en) 2009-10-02 2019-08-06 Avexxin As 2-oxothiazole compounds and method of using same for chronic inflammatory disorders
US10259801B2 (en) 2013-01-29 2019-04-16 Avexxin As Anti-inflammatory and antitumor 2-oxothiazoles ABD 2-oxothiophenes compounds
US11034666B2 (en) 2013-01-29 2021-06-15 Avexxin As Anti-inflammatory and antitumor 2-oxothiazoles and 2-oxothiophenes compounds
US11691959B2 (en) 2013-01-29 2023-07-04 Avexxin As Anti-inflammatory and antitumor 2-oxothiazoles and 2-oxothiophenes compounds
EP3135664A4 (fr) * 2014-04-21 2017-11-01 Adeka Corporation Composé alcoxyde, matière première pour former un film mince, procédé de production de film mince, et composé alcool
US10351584B2 (en) 2014-04-21 2019-07-16 Adeka Corporation Alkoxide compound, raw material for forming thin film, method for manufacturing thin film, and alcohol compound
US10150781B2 (en) 2014-08-01 2018-12-11 Avexxin As 2-oxothiatole compounds having activity as CPLA2 inhibitors for the treatment of inflammatory disorders and hyperproliferative disorders
US10851114B2 (en) 2014-08-01 2020-12-01 Avexxin As 2-oxothiatole compounds having activity as cPLA2 inhibitors for the treatment of inflammatory disorders and hyperproliferative disorders
US11439625B2 (en) 2016-03-14 2022-09-13 Avexxin As Combination therapy for proliferative diseases

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